The present invention is concerned with novel dihydroindole and tetrahydroquinoline derivatives, their manufacture and their use as medicaments.
2,3-oxidosqualene-lanosterol cyclase (EC 5.4.99.) is required for the biosynthesis of cholesterol, ergosterol and other sterols. Causal risk factors that directly promote the development of coronary and peripheral atherosclerosis include elevated low-density lipoprotein cholesterol (LDL-C), low high-density lipoprotein cholesterol (HDL-C), hypertension, cigarette smoking and diabetes mellitus. Other synergistic risk factors include elevated concentrations of triglyceride (TG)-rich lipoproteins, small, dense low-density lipoprotein particles, lipoprotein (a) (Lp(a)), and homocysteine. Predisposing risk factors modify the causal or conditional risk factors and thus affect atherogenesis indirectly. The predisposing risk factors are obesity, physical inactivity, family history of premature CVD, and male sex. The strong connection between coronary heart disease (CHD) and high LDL-C levels in plasma, and the therapeutic advantage of lowering elevated LDL-C levels are now well established (Gotto et al., Circulation 81, 1990, 1721-1733; Stein et al., Nutr. Metab. Cardiovasc. Dis. 2, 1992, 113-156; Illingworth, Med. Clin. North. Am. 84, 2000, 23-42). Cholesterol-rich, sometimes unstable, atherosclerotic plaques lead to the occlusion of blood vessels resulting in an ischemia or an infarct. Studies with respect to primary prophylaxis have shown that a lowering of plasma LDL-C levels in plasma reduces the frequency of non-fatal incidences of CHD, while the overall morbidity remains unchanged. The lowering of plasma LDL-C levels in patients with pre-established CHD (secondary intervention) reduces CHD mortality and morbidity; meta-analysis of different studies shows that this decrease is proportional to the reduction of the LDL-C (Ross et al., Arch. Intern. Med. 159, 1999, 1793-1802).
The clinical advantage of cholesterol lowering is greater for patients with pre-established CHD than for asymptomatic persons with hypercholesterolemia. According to current guidelines, cholesterol lowering treatment is recommended for patients who had survived a myocardial infarct or patients suffering from angina pectoris or another atherosclerotic disease, with a target LDL-C level of 100 mg/dl.
Preparations such as bile acid sequestrants, fibrates, nicotinic acid, probucol as well as statins, i.e. HMG-Co-A reductase inhibitors such as simvastatin and atorvastatin, are used for usual standard therapies. The best statins reduce plasma LDL-C effectively by at least 40%, and also plasma triglycerides, a synergistic risk factor, but less effectively. In contrast, fibrates reduce plasma triglycerides effectively, but not LDL-C. Combination of a statin and a fibrate proved to be very efficacious in lowering LDL-C and triglycerides (Ellen and McPherson, J. Cardiol. 81, 1998, 60B-65B), but safety of such a combination remains an issue (Shepherd, Eur. Heart J. 16, 1995, 5-13). A single drug with a mixed profile combining effective lowering of both LDL-C and triglycerides would provide additional clinical benefit to asymptomatic and symptomatic patients.
In humans, statins are well tolerated at standard dosage, but reductions in non-sterol intermediates in the cholesterol synthesis pathway, such as isoprenoids and coenzyme Q, may be associated with adverse clinical events at high doses (Davignon et al., Can. J. Cardiol. 8, 1992, 843-864; Pederson and Tobert, Drug Safety 14, 1996, 11-24).
This has stimulated the search for, and development of compounds that inhibit cholesterol biosynthesis, yet act distal to the synthesis of these important, non-sterol intermediates. 2,3-oxidosqualene:lanosterol cyclase (OSC), a microsomal enzyme, represents a unique target for a cholesterol-lowering drug (Morand et al., J. Lipid Res., 38, 1997, 373-390; Mark et al., J. Lipid Res. 37, 1996, 148-158). OSC is downstream of farnesyl-pyrophosphate, beyond the synthesis of isoprenoids and coenzyme Q. In hamsters, pharmacologically active doses of an OSC inhibitor showed no adverse side-effects, in contrast to a statin which reduced food-intake and body weight, and increased plasma bilirubin, liver weight and liver triglyceride content (Morand et al., J. Lipid Res., 38, 1997, 373-390). The compounds described in European Patent Application No. 636 367, which inhibit OSC and which lower the total cholesterol in plasma, belong to these substances.
OSC inhibition does not trigger the overexpression of HMGR because of an indirect, negative feed-back regulatory mechanism involving the production of 24(S),25-epoxycholesterol (Peffley et al., Biochem. Pharmacol. 56, 1998, 439-449; Nelson et al., J. Biol. Chem. 256, 1981, 1067-1068; Spencer et al., J. Biol. Chem. 260, 1985, 13391-13394; Panini et al., J. Lipid Res. 27, 1986, 1190-1204; Ness et al., Arch. Biochem. Biophys. 308, 1994, 420-425). This negative feed-back regulatory mechanism is fundamental to the concept of OSC inhibition because (i) it potentiates synergistically the primary inhibitory effect with an indirect down-regulation of HMGR, and (ii) it prevents the massive accumulation of the precursor monooxidosqualene in the liver. In addition, 24(S),25-epoxycholesterol was found to be one of the most potent agonists of the nuclear receptor LXR (Janowski et al., Proc. Natl. Acad. Sci. USA, 96, 1999, 266-271). Considering that 24(S),25-epoxycholesterol is a by-product of inhibition of OSC it is hypothesized that the OSC inhibitors of the present invention could also indirectly activate LXR-dependent pathways such as (i) cholesterol-7alpha-hydroxylase to increase the consumption of cholesterol via the bile acid route, (ii) expression of ABC proteins with the potential to stimulate reverse cholesterol transport and increase plasma HDL-C levels (Venkateswaran et al., J. Biol. Chem. 275, 2000, 14700-14707; Costet et al., J. Biol. Chem. June 2000, in press; Ordovas, Nutr Rev 58, 2000, 76-79, Schmitz and Kaminsky, Front Biosci 6, 2001, D505-D514), and/or inhibit intestinal cholesterol absorption (Mangelsdorf, XIIth International Symposium on Atherosclerosis, Stockholm, June 2000). In addition, possible cross talks between fatty acid and cholesterol metabolism mediated by liver LXR have been hypothesized (Tobin et al., Mol. Endocrinol. 14, 2000, 741-752).
The invention relates to compounds of the formula (I) 
wherein
U is O or a lone pair,
V is a) O, S, NR1, or CH2, and L is lower-alkylene or lower-alkenylene,
b) xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94, and L is lower-alkylene or a single bond,
W is CO, COO, CONR2, CSO, CSNR2, SO2, or SO2NR2,
X is hydrogen or one or more optional halogen and/or lower-alkyl substituents,
m is 1 or 2,
n is 0 to 7,
A1 is hydrogen, lower-alkenyl, or lower-alkyl optionally substituted by hydroxy, lower-alkoxy, or thio-lower-alkoxy,
A2 is cycloalkyl, cycloalkyl-lower-alkyl, lower-alkenyl, lower-alkinyl, or lower-alkyl optionally substituted by hydroxy, lower-alkoxy or thio-lower-alkoxy,
A3 and A4 independently from each other are hydrogen or lower-alkyl, or
A1 and A2 or A1 and A3 are bonded to each other to form a ring and xe2x80x94A1xe2x80x94A2xe2x80x94 or xe2x80x94A1xe2x80x94A3xe2x80x94 are lower-alkylene or lower-alkenylene, optionally substituted by R3, in which one xe2x80x94CH2xe2x80x94 group of xe2x80x94A1-A2xe2x80x94 or xe2x80x94A1xe2x80x94A3xe2x80x94 can optionally be replaced by NR4, S, or O,
A5 is cycloalkyl, cycloalkyl-lower-alkyl, heterocycloalkyl-lower-alkyl, aryl, aryl-lower-alkyl, heteroaryl, heteroaryl-lower-alkyl, lower-alkyl optionally substituted with hydroxy or lower-alkoxy, alkenyl optionally substituted with hydroxy, or alkadienyl optionally substituted with hydroxy,
R3 is hydroxy, lower-alkoxy, thio-lower-alkoxy, N(R5, R6), or lower-alkyl optionally substituted by hydroxy,
R1, R2, R4, R5, and R6 independently from each other are hydrogen or lower-alkyl, and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
The compounds of formula I inhibit OSC and therefore also inhibit the biosynthesis of cholesterol, ergosterol and other sterols, and reduce the plasma cholesterol levels. They can therefore be used in the therapy and prophylaxis of hypercholesterolemia, hyperlipemia, arteriosclerosis and vascular diseases in general. Furthermore, they can be used in the therapy and/or prevention of mycoses, parasite infections, gallstones, cholestatic liver disorders, tumors and hyperproliferative disorders, e.g. hyperproliferative skin and vascular disorders. In addition, it has unexpectedly been found that the compounds of the present invention can also be of therapeutical use to improve glucose tolerance in order to treat and/or prevent related diseases such as diabetes. The compounds of the present invention further exhibit improved pharmacological properties compared to known compounds.
Unless otherwise indicated the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
In this specification the term xe2x80x9clowerxe2x80x9d is used to mean a group consisting of one to seven, preferably of one to four carbon atom(s).
The term xe2x80x9clone pairxe2x80x9d refers to an unbound electron pair, in particular to the unbound electron pair of a nitrogen atom in e.g. an amine.
The term xe2x80x9chalogenxe2x80x9d refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.
The term xe2x80x9cprotecting groupxe2x80x9d refers to groups such as acyl, azoyl, alkoxycarbonyl, aryloxycarbonyl, or silyl. Examples are e.g. t-butyloxycarbonyl, benzyloxycarbonyl or fluorenylmethyloxycarbonyl which can be used for the protection of amino groups or trimethylsilyl, dimethyl-tert-butyl-silyl or tert.-butyl-diphenyl-silyl, which can be used for the protection of hydroxy groups, trityl or p-methoxybenzyl for sulfur, methyl or benzyl for the protection of phenole derivatives, methyl, ethyl or tert.-butyl for the protection of thiophenole derivatives.
The term xe2x80x9calkylxe2x80x9d, alone or in combination with other groups, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms. Lower-alkyl groups as described below also are preferred alkyl groups. Alkyl groups can be substituted e.g. with halogen, hydroxy, lower-alkoxy, thio-lower-alkoxy, lower-alkoxy-carbonyl, NH2, and/or N(lower-alkyl)2.
The term xe2x80x9clower-alkylxe2x80x9d, alone or in combination with other groups, refers to a branched or straight-chain monovalent alkyl radical of one to seven carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like. A lower-alkyl group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a monovalent carbocyclic radical of 3 to 10 carbon atom(s), preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Cycloalkyl in which one or more xe2x80x94CH2xe2x80x94 group is replaced by O, S, NH and/or N(lower-alkyl) are referred to as xe2x80x9cheterocycloalkylxe2x80x9d. Examples of heterocycloalkyl groups are e.g. tetrahydrofuryl, pyrrolidinyl, piperidyl, and morpholinyl.
The term xe2x80x9calkoxyxe2x80x9d refers to the group Rxe2x80x2xe2x80x94Oxe2x80x94, wherein Rxe2x80x2 is an alkyl. The term xe2x80x9clower-alkoxyxe2x80x9d refers to the group Rxe2x80x2xe2x80x94Oxe2x80x94, wherein Rxe2x80x2 is a lower-alkyl. The term xe2x80x9cthio-alkoxyxe2x80x9d refers to the group Rxe2x80x2xe2x80x94Sxe2x80x94, wherein Rxe2x80x2 is an alkyl. The term xe2x80x9cthio-lower-alkoxyxe2x80x9d refers to the group Rxe2x80x2xe2x80x94Sxe2x80x94, wherein Rxe2x80x2 is a lower-alkyl.
The term xe2x80x9calkenylxe2x80x9d, alone or in combination with other groups, stands for a straight-chain or branched hydrocarbon residue comprising an olefinic bond and up to 20, preferably up to 16 carbon atoms, more preferrably up to 10 carbon atoms. Lower-alkenyl groups as described below also are preferred alkenyl groups. The term xe2x80x9clower-alkenylxe2x80x9d refers to a straight-chain or branched hydrocarbon residue comprising an olefinic bond and up to 7, preferably up to 4 carbon atoms, such as e.g. 2-propenyl. An alkenyl or lower-alkenyl group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d.
The term xe2x80x9calkadienylxe2x80x9d, alone or in combination with other groups, stands for a straight-chain or branched hydrocarbon residue comprising 2 olefinic bonds and up to 20, preferably up to 16 carbon atoms, more preferably up to 10 carbon atoms. Lower-alkadienyl groups as described below also are preferred alkadienyl groups. The term xe2x80x9clower-alkadienylxe2x80x9d refers to a straight-chain or branched hydrocarbon residue comprising 2 olefinic bonds and up to 7 carbon atoms. An alkadienyl or lower-alkadienyl group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d.
The term xe2x80x9calkinylxe2x80x9d, alone or in combination with other groups, stands for a straight-chain or branched hydrocarbon residue comprising a triple bond and up to 20, preferably up to 16 carbon atoms. The term xe2x80x9clower-alkinylxe2x80x9d refers to a straight-chain or branched hydrocarbon residue comprising a triple bond and up to 7, preferably up to 4 carbon atoms, such as e.g. 2-propinyl. An alkinyl or lower-alkinyl group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d.
The term xe2x80x9calkylenexe2x80x9d refers to a straight chain or branched divalent saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 16 carbon atoms. The term xe2x80x9clower-alkylenexe2x80x9d refers to a straight chain or branched divalent saturated aliphatic hydrocarbon group of 1 to 7, preferably 1 to 6 or 3 to 6 carbon atoms. Straight chain alkylene or lower-alkylene groups are preferred. An alkylene or lower-alkylene group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d.
The term xe2x80x9calkenylenexe2x80x9d refers to a straight chain or branched divalent hydrocarbon group comprising an olefinic bond and up to 20 carbon atoms, preferably up to 16 carbon atoms. The term xe2x80x9clower-alkenylenexe2x80x9d refers to a straight chain or branched divalent hydrocarbon group comprising an olefinic bond and up to 7, preferably up to 5, C-atoms. Straight chain alkenylene or lower-alkenylene groups are preferred. An alkenylene or lower-alkenylene group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d.
The term xe2x80x9carylxe2x80x9d relates to the phenyl or naphthyl group, preferably the phenyl group, which can optionally be mono- or multiply-substituted by lower-alkyl, lower-alkinyl, dioxo-lower-alkylene (forming e.g. a benzodioxyl group), halogen, hydroxy, CN, CF3, NH2, N(H, lower-alkyl), N(lower-alkyl)2, aminocarbonyl, carboxy, NO2, lower-alkoxy, thio-lower-alkoxy, lower-alkylcarbonyl, lower-alkylcarbonyloxy, lower-alkoxycarbonyl, aryl, and/or aryloxy. Preferred substituents are halogen, CF3, NO2, CN, lower-alkyl, lower-alkoxy, thio-lower-alkoxy, lower-alkoxycarbonyl, and/or lower-alkylcarbonyl. More preferred substituents are fluorine and chlorine.
The term xe2x80x9cheteroarylxe2x80x9d refers to an aromatic 5- or 6-membered ring which can comprise 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulphur such as furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thienyl, isoxazolyl, oxazolyl, imidazolyl, or pyrrolyl. The term xe2x80x9cheteroarylxe2x80x9d further refers to bicyclic aromatic groups comprising two 5- or 6-membered rings, in which one or both rings can contain 1, 2 or 3 atoms selected from nitrogen, oxygen or sulphur such as e.g. indol or chinolin, or partially hydrogenated bicyclic aromatic groups such as e.g. indolinyl. A heteroaryl group may have a substitution pattern as described earlier in connection with the term xe2x80x9carylxe2x80x9d. Preferred heteroaryl groups are thienyl and pyridyl which can optionally be substituted as described above, preferably with bromine.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d embraces salts of the compounds of formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms. Preferred salts are formates, hydrochlorides, hydrobromides and methanesulfonic acid salts.
The term xe2x80x9cpharmaceutically acceptable estersxe2x80x9d embraces esters of the compounds of formula (I), in which hydroxy groups have been converted to the corresponding esters with inorganic or organic acids such as nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms.
In detail, the present invention relates to compounds of formula (I) 
wherein
U is O or a lone pair,
V is a) O, S, NR1, or CH2, and L is lower-alkylene or lower-alkenylene,
b) xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94, and L is lower-alkylene or a single bond,
W is CO, COO, CONR2, CSO, CSNR2, SO2, or SO2NR2,
X is hydrogen or one or more optional halogen and/or lower-alkyl substituents,
m is 1 or 2,
n is 0 to 7,
A1 is hydrogen, lower-alkenyl, or lower-alkyl optionally substituted by hydroxy, lower-alkoxy, or thio-lower-alkoxy,
A2 is cycloalkyl, cycloalkyl-lower-alkyl, lower-alkenyl, lower-alkinyl, or lower-alkyl optionally substituted by hydroxy, lower-alkoxy or thio-lower-alkoxy,
A3 and A4 independently from each other are hydrogen or lower-alkyl, or
A1 and A2 or A1 and A3 are bonded to each other to form a ring and xe2x80x94A1xe2x80x94A2xe2x80x94 or
xe2x80x94A1xe2x80x94A3xe2x80x94 are lower-alkylene or lower-alkenylene, optionally substituted by R3, in which one xe2x80x94CH2xe2x80x94 group of xe2x80x94A1xe2x80x94A2xe2x80x94 or xe2x80x94A1xe2x80x94A3xe2x80x94 can optionally be replaced by NR4, S, or O,
A5 is cycloalkyl, cycloalkyl-lower-alkyl, heterocycloalkyl-lower-alkyl, aryl, aryl-lower-alkyl, heteroaryl, heteroaryl-lower-alkyl, lower-alkyl optionally substituted with hydroxy or lower-alkoxy, alkenyl optionally substituted with hydroxy, or alkadienyl optionally substituted with hydroxy,
R3 is hydroxy, lower-alkoxy, thio-lower-alkoxy, N(R5, R6), or lower-alkyl optionally substituted by hydroxy,
R1, R2, R4, R5, and R6 independently from each other are hydrogen or lower-alkyl, and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
Preferred are compounds of formula (I) and/or pharmaceutically acceptable salts thereof. Other preferred embodiments relate to compounds of formula (I) wherein U is a lone pair or to compounds of formula (I) wherein U is O.
Each of the definitions of V given above, a) and b), individually constitutes a preferred embodiment of the present invention. Further, each of the definitions of L, lower-alkylene, lower-alkenylene and a single bond, individually constitutes a preferred embodiment of the present invention. Compounds as described above in which V is O or CH2 and L is lower-alkylene or lower-alkenylene relate to a further preferred embodiment of the present invention. Other preferred compounds are those, wherein V is xe2x80x94Cxe2x89xa1Cxe2x80x94 and L is lower-alkylene or a single bond. Compounds as described above, wherein n is 0 also relate to a preferred embodiment of the present invention. Compounds as decsribed above, in which the number of carbon atoms of L and (CH2)o together is 10 or less, more preferably 7 or less, are also preferred. The groups of compounds as described above, in which m is 1 or m is 2 individually relate to a preferred embodiment of the present invention.
Other preferred compounds of the present invention are those in which A1 represents lower-alkyl, preferrably those in which A1 is methyl or ethyl. Another group of preferred compounds of the present invention are those in which A2 represents lower-alkenyl, or lower-alkyl optionally substituted by hydroxy or lower-alkoxy, with those compounds wherein A2 represents 2-propenyl or 2-hydroxy-ethyl being especially preferred.
Compounds of formula (I), wherein A1 and A2 are bonded to each other to form a ring and xe2x80x94A1xe2x80x94A2xe2x80x94 is lower-alkylene or lower-alkenylene, optionally substituted by R3, in which one xe2x80x94CH2xe2x80x94 group of xe2x80x94A1xe2x80x94A2xe2x80x94 can optionally be replaced by NR4, S, or O, wherein R3 and R4 are as defined above are also preferred. In compounds wherein A1 and A2 are bonded to each other to form a ring, said ring is preferrably a 4-, 5-, or 6-membered ring such as e.g. piperidinyl or pyrrolidinyl.
A further preferred embodiment of the present invention relates to compounds of formula (I), wherein A3 and/or A4 represent hydrogen.
Compounds of formula (I), wherein A5 cycloalkyl, cycloalkyl-lower-alkyl, heterocycloalkyl-lower-alkyl, aryl, aryl-lower-alkyl, heteroaryl, heteroaryl-lower-alkyl, or lower-alkyl optionally substituted with hydroxy or lower-alkoxy represent a preferred embodiment of the present invention. Other preferred compounds are those in which A5 is phenyl or benzyl, optionally substituted by 1 to 3 substituents independently selected from the group consisting of fluorine and chlorine, or wherein A5 is lower-alkyl, with those compounds wherein A5 is phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, butyl, or pentyl being particularly preferred. Another preferred group relates to compounds wherein X is hydrogen. Another preferred group relates to compounds wherein X is fluorine.
Compounds in which R2 is hydrogen are also preferred. A further preferred embodiment of the present invention relates to those compounds as defined above, wherein W is COO, CONR2, CSO, or CSNR2 and R2 is hydrogen.
Preferred compounds of general formula (I) are those selected from the group consisting of:
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid (2,4-difluoro-phenyl)-amide,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid (4-fluoro-phenyl)-amide,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid p-tolylamide,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid (4-bromo-phenyl)-amide,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid (2,4-dimethoxy-phenyl)-amide,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid (4-methoxy-phenyl)-amide,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid naphthalen-2-ylamide,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid (4-acetyl-phenyl)-amide,
{5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indol-1-yl}-(4-bromo-phenyl)-methanone,
3-{5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbonyl}-benzonitrile,
{5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indol-1-yl}-(4-fluoro-phenyl)-methanone,
{5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indol-1-yl}-(5-bromo-thiophen-2-yl)-methanone,
{5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indol-1-yl}-(4-chloro-phenyl)-methanone,
{5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indol-1-yl}-phenyl-methanone,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid (4-chloro-phenyl)-amide,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid cycloheptylamide,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid cyclohexylmethyl-amide,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid 4-chloro-benzylamide,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid (4-trifluoromethyl-phenyl)-amide,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid 4-fluoro-benzylamide,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid O-(4-fluoro-phenyl)ester,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid O-(4-chloro-phenyl)ester,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid O-p-tolyl ester,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid O-phenyl ester,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-sulfonic acid phenylamide,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-sulfonic acid (4-chloro-phenyl)-amide,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-sulfonic acid (2,4-difluoro-phenyl)-amide,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-sulfonic acid (4-fluoro-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic acid (2,4-difluoro-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic acid (4-fluoro-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic acid p-tolylamide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic acid (4-bromo-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic acid (2,4-dimethoxy-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic acid (4-methoxy-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic acid naphthalen-2-ylamide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic acid (4-acetyl-phenyl)-amide,
{5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indol-1-yl}-(4-bromo-phenyl)-methanone,
3-{5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbonyl}-benzonitrile,
{5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indol-1-yl}-(4-fluoro-phenyl)-methanone,
{5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indol-1-yl}-(5-bromo-thiophen-2-yl)-methanone,
{5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indol-1-yl}-(4-chloro-phenyl)-methanone,
{5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indol-1-yl}-phenyl-methanone,
{5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indol-1-yl}-(4-trifluoromethyl-phenyl)-methanone,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid (4-chloro-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid cycloheptylamide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid cyclohexylmethyl-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid 4-chloro-benzylamide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid (4-trifluoromethyl-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid 4-fluoro-benzylamide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid benzylamide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid cyclohexylamide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid O-(4-chloro-phenyl)ester,
5-{4-[(2-Methoxy-ethyl)-methyl-amino]-butoxy}-2,3-dihydro-indole-1-carbothioic acid O-(4-chloro-phenyl)ester,
5-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-2,3-dihydro-indole-1-carbothioic acid O-(4-chloro-phenyl)ester,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid O-(4-fluoro-phenyl)ester,
Allyl-{5-[1-(4-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-pentyl}methyl-amine,
Allyl-{5-[1-(4-bromo-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-pentyl}-methyl-amine,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester,
Allyl-{4-[1-(4-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-6-yloxy]-but-2-enyl}-methyl-amine,
6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester,
Allyl-{5-[1-(4-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-6-yloxy]-pentyl}-methyl-amine,
6-[3-(Allyl-methyl-amino)-propoxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester,
6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid (4-methoxy-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid p-tolylamide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid naphthalen-1-ylamide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid (2,4-difluoro-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid (4-fluoro-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid (2,4-dimethoxy-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid (4-methylsulfanyl-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid (4-bromo-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid benzylamide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid (4-butyl-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid (4-acetyl-phenyl)-amide,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester.
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid p-tolylamide,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid (4-fluoro-phenyl)-amide,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid (4-bromo-phenyl)-amide,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid (4-butyl-phenyl)-amide,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-bromo-phenyl ester,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-fluoro-phenyl ester,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid p-tolyl ester,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid hexyl ester,
3-{6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carbonyl}-benzonitrile,
{6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-bromo-phenyl)-methanone,
{6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(5-bromo-thiophen-2-yl)-methanone,
{6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-fluoro-phenyl)-methanone,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-methoxy-phenyl ester,
3-{6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carbonyl}-benzonitrile,
{6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-bromo-phenyl)-methanone,
1-{6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-2-(2,4-difluoro-phenyl)-ethanone,
1-(4-{6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-ethanone,
{6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(5-bromo-thiophen-2-yl)-methanone,
{6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(3-chloro-phenyl)-methanone,
1-{6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-2-(4-fluoro-phenyl)-ethanone,
{6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-fluoro-phenyl)-methanone,
{6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-chloro-phenyl)-methanone,
{6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-trifluoromethyl-phenyl)-methanone,
{6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-pyridin-3-yl-methanone,
{6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-fluoro-3-methyl-phenyl)-methanone,
6-[4-(allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-nitro-phenyl ester,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid hexyl ester,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-bromo-phenyl ester,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid isobutyl ester,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid phenyl ester,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-methoxy-phenyl ester,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid p-tolyl ester,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-methoxycarbonyl-phenyl ester,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid butyl ester,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-fluoro-phenyl ester,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid phenethyl-amide,
6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester,
6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester,
6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-bromo-phenyl ester,
6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid hexyl ester,
6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid (4-fluoro-phenyl)-amide,
6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid p-tolylamide,
6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid (4-bromo-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid (2,4-difluoro-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid (4-fluoro-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid p-tolylamide,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid (4-bromo-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid (2,4-dimethoxy-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid (4-methoxy-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid naphthalen-2-ylamide,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid (4-acetyl-phenyl)-amide,
6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-fluoro-phenyl ester,
{6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-bromo-phenyl)-methanone,
3-{6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbonyl}-benzonitrile,
{6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-fluoro-phenyl)-methanone,
{6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinolin-1-yl}-(5-bromo-thiophen-2-yl)-methanone,
{6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H -quinolin-1-yl}-(4-chloro-phenyl)-methanone,
{6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinolin-1-yl}-phenyl-methanone,
{6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-trifluoromethyl-phenyl)-methanone,
(4-Bromo-phenyl)-[6-(4-diethylamino-butoxy)-3,4-dihydro-2H-quinolin-1-yl]-methanone,
3-[6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carbonyl]-benzonitrile,
[6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinolin-1-yl]-(4-fluoro-phenyl)-methanone,
(5-Bromo-thiophen-2-yl)-[6-(4-diethylamino-butoxy)-3,4-dihydro-2H-quinolin-1-yl]-methanone,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic acid (4-chloro-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic acid cycloheptylamide,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic acid cyclohexylmethyl-amide,
6-[4-(Allyl-methyl-amino)-butoxy]-3)4-dihydro-2H-quinoline-1-carbothioic acid 4-chloro-benzylamide,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic acid (4-trifluoromethyl-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic acid 4-fluoro-benzylamide,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic acid benzylamide,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic acid cyclohexylamide,
6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carbothioic acid O-(4-fluoro-phenyl) ester,
6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carbothioic acid O-(4-chloro-phenyl) ester,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic acid O-(4-fluoro-phenyl) ester,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic acid O-(4-chloro-phenyl)ester,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic acid O-phenyl ester,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid phenylamide,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (4-chloro-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (2,4-difluoro-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (4-fluoro-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid (4-chloro-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid p-tolylamide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid (4-cyano-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid (4-methoxy-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid (3,4-difluoro-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid (3-fluoro-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid (2,4-difluoro-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid (2,5-difluoro-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid (4-bromo-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid phenylamide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid (3-methyl-butyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid (furan-2-ylmethyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid ethylamide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid butylamide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid (2-methyl-butyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid (2-methoxy-ethyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid (4-butyl-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid (tetrahydro-furan-2-ylmethyl)-amide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (4-chloro-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (4-fluoro-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (4-bromo-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (p-tolyl)-amide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid
(3,4-difluoro-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (4-trifluoromethyl-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (3-fluoro-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (4-cyano-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (2,4-difluoro-phenyl)-amide, 6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (4-methoxy-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (2,5-difluoro-phenyl)-amide,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (phenyl)-amide,
6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (4-chloro-phenyl)-amide,
6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (4-cyano-phenyl)-amide,
6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (3-fluoro-phenyl)-amide,
6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (4-bromo-phenyl)-amide,
6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (4-methoxy-phenyl)-amide,
6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (2,4-difluoro-phenyl)-amide,
6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid p-tolylamide,
6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (4-fluoro-phenyl)-amide,
6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (2,5-difluoro-phenyl)-amide,
6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (4-trifluoromethyl-phenyl)-amide,
6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (3,4-difluoro-phenyl)-amide,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carbothioic acid (4-chloro-phenyl)-amide,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (4-cyano-phenyl)-amide,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carbothioic acid cycloheptylamide,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (4-methoxy-phenyl)-amide,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (4-chloro-phenyl)-amide,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (2,5-difluoro-phenyl)-amide,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (4-bromo-phenyl)-amide,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (2,4-difluoro-phenyl)-amide,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid p-tolylamide,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid butylamide,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid (3-fluoro-phenyl)-amide,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic acid phenylamide,
5-[4-(Allyl-methyl-amino)-but-2-enyloxy]-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester,
5-{4-[(2-Methoxy-ethyl)-methyl-amino]-butoxy}-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester,
5-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester,
6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester,
6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester,
6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester, and
6-[5-(Allyl-methyl-amino)-pentyl]-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester
and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
Further preferred compounds of general formula (I) are those selected from the group consisting of
5-[5-(Allyl-methyl-amino)-pent-1-ynyl]-6-fluoro-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester,
6-Fluoro-5-{5-[(2-hydroxy-ethyl)-methyl-amino]-pent-1-ynyl}-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester,
5-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pent-1-ynyl}-6-fluoro-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester,
2-({5-[6-Fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-ynyl}-methyl-amino)-ethanol,
2-(Ethyl-{5-[6-fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-ynyl}-amino)-ethanol,
6-Fluoro-5-[5-(methyl-propyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid phenyl ester,
2-({5-[6-Fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pentyl}-methyl-amino)-ethanol,
and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
Further particularly preferred compounds of general formula (I) are those selected from the group consisting of
5-[5-(Allyl-methyl-amino)-pent-1-ynyl]-6-fluoro-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester,
5-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pent-1-ynyl}-6-fluoro-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester,
6-Fluoro-5-[5-(methyl-propyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid phenyl ester,
and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
Still more preferred embodiments of the invention are those of general formula (VII) 
wherein
V is O or Ch2;
L is lower-alkylene or lower-alkenylene;
W is COO, CONH, CSNH or CSO;
A1 is hydrogen or lower-alkyl;
A2 is lower alkyl or lower alkenyl;
m is 1 or 2; and
A5 is lower alkyl, phenyl or lower alkyl phenyl, wherein the phenyl group is optionally substituted with halogen;
and pharmaceutically acceptable salts and esters thereof.
Preferred compounds of general formula (VII) are those selected from the group consisting of
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid O-(4-chloro-phenyl)ester,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid O-(4-chloro-phenyl)ester,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester,
6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid (4-fluoro-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid 4-fluoro-benzylamide,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid 4-chloro-benzylamide,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid (4-fluoro-phenyl)-amide,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid O-(4-fluoro-phenyl)ester,
5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid (4-chloro-phenyl)-amide,
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid (2-methyl-butyl)-amide, and
5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid butylamide,
and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
Compounds of formulas (I) and (VII) can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers or as racemats. The invention embraces all of these forms.
It will be appreciated, that the compounds of general formula (I) in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.
The present invention also relates to a process for the manufacture of compounds as described above, which process comprises
reacting a compound of formula (II) 
with a compound (A1, A2, U)Nxe2x80x94C(A3, A4)xe2x80x94Lxe2x80x94M, wherein V is O, S or NR1, M is mesylate, tosylate, triflate, Cl, Br or I, and U, A1, A2, A3, A4, A5, L, W, X, m, n and R1 are as defined above, or wherein HV is mesylate, tosylate, triflate, Cl, Br or I, and M is OH, SH or NHR1, and
R1 is as defined above,
or b) reacting a compound of formula (III) 
with a compound NHA1, A2, wherein M is mesylate, tosylate, triflate, Cl, Br or I, and A1, A2, A3,
A4, A5, L, V, W, X, m and n are as defined above,
or c) reacting a compound of formula (IV) 
with a compound (A1, A2, U)Nxe2x80x94C(A3, A4)xe2x80x94Lxe2x80x94Cxe2x89xa1CH, wherein M is Br or F3CO2SO, and U, A1, A2,
A3, A4, A5, L, W, X and m are as defined above,
or d) reacting a compound of formula (V) 
with a compound (A1, A2, U)Nxe2x80x94C(A3, A4)xe2x80x94Lxe2x80x94M, wherein M is mesylate, tosylate, triflate, Cl, Br
or I, and A1, A2, A3, A4, A5, W, U, L, X, m and n are as defined above,
or e) hydrogenating a compound of formula (VI) 
wherein V is xe2x80x94Cxe2x89xa1Cxe2x80x94, and A1, A2, A3, A4, A5, U, W, L, X, m and n are as defined above,
and optionally converting a compound according to any of claims 1 to 21 to a pharmaceutically acceptable salt,
and optionally converting a compound according to any of claims 1 to 21, wherein U is a lone pair, to a corresponding compound wherein U is O.
The invention further relates to compounds of formula (I) as defined above, when manufactured according to a process as defined above.
As described above, the compounds of formula (I) of the present invention can be used for the treatment and/or prophylaxis of diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections and gallstones, and/or treatment and/or prophylaxis of impaired glucose tolerance, diabetes, tumors and/or hyperproliferative disorders, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia. Hyperproliferative skin and vascular disorders particularly come into consideration as hyperproliferative disorders.
The invention therefore also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.
Further, the invention relates to compounds as defined above for use as therapeutic active substances, particularly as therapeutic active substances for the treatment and/or prophylaxis of of diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/or hyperproliferative disorders, and/or treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia.
In another embodiment, the invention relates to a method for the treatment and/or prophylaxis of diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/or hyperproliferative disorders, and/or treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia, which method comprises administering a compound as defined above to a human being or animal.
The invention further relates to the use of compounds as defined above for the treatment and/or prophylaxis of diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/or hyperproliferative disorders, and/or treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia.
In addition, the invention relates to the use of compounds as defined above for the preparation of medicaments for the treatment and/or prophylaxis of diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/or hyperproliferative disorders, and/or treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia. Such medicaments comprise a compound as defined above.
The compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to the person skilled in the art. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below or in the examples or by methods known in the art, e.g. by methods described in: Richard J. Sundberg Indoles (Best Synthetic Methods), Series Editor A. R. Katritzky, O. Meth-Cohn, C. W. Rees, Academic Press, San Diego 1996, or inHouben-Weyl Methoden der Organischen Chemie, R. P. Kreker, Ed., Georg Thieme Verlag, Stuttgart, 1994, or The Chemistry of Heterocyclic Compounds. A Series of Monographs, Vol. 32, Quinolines. Part 1-3, Weissenberger, E. C. Taylor, G. Jones, Eds, Wiley, London. 
Scheme 1
If starting material 1 is a tetrahydroquinoline derivative (m=2), it may be derived from the corresponding quinoline derivative by hydrogenation with PtO2 in a suitable solvent such as methanol, ethanol. If starting material 1 is an indoline derivative (m=1), it maybe derived from the corresponding indole derivative for example by treatment with NaCNBH3 in acetic acid or trifluoro acetic acid or by employing other methods known in the art.
Derivative 1 is either N-protected (e.g. (BOC)2O, CH2Cl2) to yield compound 2 or is directly converted to the desired A5W-substituted derivative 2 using one of the methods described later for compound 5.
Deprotection of the V-group can be achieved, if 2 is a 5-benzyloxyindoline derivative, by hydrogenation with e.g. Pd/C in solvents like methanol, ethanol or ethyl acetate, if 2 is a 5-methoxy-indoline derivative, by treatment for example with lithium-tri-sec-butylborohydride in THF. For Vxe2x95x90S, NR1 or Vxe2x95x90O and n greater than 0, deprotection using procedures known in the art (step c) yields the building block 3.
Alkylation of the phenol/thiophenol 3 (Vxe2x95x90O, S, n=0) is accomplished in acetone or DMF with K2CO3 and a suitable dihaloalkane or dihaloalkene (halogene is here represented by bromine, but can also be chlorine or iodine. It is also possible to use mesylates, tosylates or triflates instead of halogenides) at reflux to yield halogenide 4 (step c). For the preparation of derivatives 4 (Vxe2x95x90O, n greater than 0), the alcohol 3 can be treated with xcex1,xcfx89-dihaloalkanes or xcex1,xcfx89-dihaloalkenes under phase transfer conditions e.g. xcex1,xcfx89-dihaloalkanes/dihaloalkenes, NaOH, nBu4NHSO4. For Vxe2x95x90S, O or NR1, the derivative 3 may be treated with xcex1,xcfx89-dihaloalkane in the presence of NaH in DMF 0xc2x0 C. to RT to yield bromide 4. For shorter alkanes (methyl, ethyl), the method of choice is the in situ generation of the haloalkane-triflate (from the corresponding haloalkanol with trifluoromethansulfonic anhydride/2,6-di-tert-butylpyridine in CH2Cl2 at 0xc2x0 C.). This haloalkane-triflate may then be reacted with 3 in the presence of a base such as 2,6-di-tert-butylpyridine in nitromethane at 60xc2x0 C. to yield bromide 4 [analogously to a procedure of Belostotskii, Anatoly M.; Hassner, Alfred. Synthetic methods. 41. Etherification of hydroxysteroids via triflates. Tetrahedron Lett. (1994), 35(28), 5075].
Compound 4 can be converted to the amine 5 with an excess of the corresponding amine NHA1A2 in a suitable solvent such as DMA, DMF, MeOH at RT or at 50-65xc2x0 C. or by treatment with NHA1A2, NaH in solvents such as DMF or THF (step d).
Compound 5 can be N-deprotected using TFA in CH2Cl2 for BOC-groups or by hydrogenation in methanol, ethanol or ethyl acetate with Pd/C for Z-groups.
The resulting amine (not shown in scheme 1) may be treated according to one of the following procedures to yield the appropriate A5W-substituted derivative 5 (separation by HPLC was necessary in some cases).
Sulfonamides: Sulfonylation of the amines is done in dioxane or CH2Cl2 with Huenig""s base and a sulfonyl chloride over night at RT to yield the sulfonamide 5.
Carbamates: The amines may be reacted with A5OCOCl/Huenig""s base or pyridine in dioxane, THF, DMF or CH2Cl2. Alternatively, the chloroformates may be prepared in situ by treatment of A5OH with Cl3COCl in the presence of quinoline followed by reaction with the amines in the presence of Huenig""s base.
Thiocarbamates: The amines may be reacted with A5OCSCl in dioxane.
Ureas: The amines may be reacted with isocyanate in dioxane at room temperature.
Thioureas: The amines maybe reacted with isothiocyanate in dioxane at room temperature.
Amides: The amines may be reacted with A5COOH/EDCI/DMAP (with anhydride formation, and subsequent addition of the starting amine at xe2x88x9210xc2x0 C. to room temperature) or alternatively with A5COOH/EDCI/DMAP or A5COOH/Huenig""s base/EDCI/HOBT in DMF, dioxane or CH2Cl2 at room temperature.
Sulfamides: The amines may be reacted with sulfamoyl chlorides in dioxane in the presence of an excess of triethylamine to yield sulfamide 5. The sulfamoyl chlorides can be prepared from A5NH2 and chlorosulfonic acid in CH2Cl2 at 0xc2x0 C. to room temperature followed by reaction with PCl5 in toluene at 75xc2x0 C. Alternatively, the sulfamoyl chlorides can be synthesized in acetonitrile with A5NH2 and sulfuryl chloride at 0xc2x0 C. to 65xc2x0 C.
Alternatively, the compound 3 may be converted to the amine 5 by attaching the pre-assembled fragment A1A2NC(A3A4)LVxe2x80x94OMes/halogenide/triflates, which can be synthesised by known methods (shown e.g. in Scheme 2), using alkylating conditions (step f). Compounds 3 (Vxe2x95x90O, n greater than 0) can also be mesylated (Vxe2x95x90OMes) and then reacted with A1A2NC(A3A4)Lxe2x80x94VH (synthesis as described in Scheme 2) in e.g. DMF with NaH as base to yield 5 (with Vxe2x95x90O, S, NR1).
Amine 5 may be converted to a salt or to the N-oxide 6 (step e). For N-oxide 6 (Vxe2x95x90O) a mixture of hydrogen peroxide urea adduct and phthalic anhydride in CH2Cl2 at RT may be used. For the preparation of the N-oxides 6 (Vxe2x95x90S or NR1) an alternative route has to be employed (step g): Oxidation of the pre-assembled fragment A1A2NC(A3A4)Lxe2x80x94OMes/halogenide to the corresponding N-oxide derivative, followed by alkylation of the compound 3 to give compound 6 directly.
If WA5 is a protective group, this may be cleaved as described for derivative 5 and the final moieties WA5 may be introduced as described above.
Scheme 2
Scheme 2 shows the synthesis of amino-VH sidechain 24 that may be used for the synthesis of compounds with the corresponding V-spacers (Vxe2x95x90NR4, S, or O). xcex1,xcfx89-dihaloalkane, mesyl-alkanyl-halogenide, xcex1,xcfx89-dihaloalkene, mesyl-alkenyl-halogenide 21 may be treated with a suitable protected amine (HNR1-PG, PG=protecting group, e.g. BOC) in DMA or a thiol (HS-PG e.g., triphenylmethanethiol) in the presence of NaH in DMA to yield the compound 22(step a). Treatment with the amine A1A2NH yields the S- or N-protected amine 23 (step b) or in the case of xcex1,xcfx89-haloalkanol or xcex1,xcfx89-haloalkenol 21 directly amino-alcohol 24. N-deprotection with procedures known in the art e.g. TFA in CH2Cl2 yields the amine side chain 24 (step c). The deprotection of the thiol moiety in 23 may be achieved with TFA/triisopropylsilane in CH2Cl2 at 0xc2x0 C. to RT to yield the aminothiol 24 (step c). Aminoalkanol 24 can be transformed further to mesylate 25 (step d).
Scheme 3
In Scheme 3, the preparation of compounds of formula 6, in which V represents xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94 is outlined. The starting material is derivative 3, which may be converted to the triflate 32a in pyridine with trifluoromethanesulfonic anhydride at 0xc2x0 C. to RT (step a). Sonogashira-coupling (step b) of the triflate 32a and a suitable alkynol or alkynechloride in piperidine with Pd(PPh3)4/CuI at 45xc2x0 C. to 80xc2x0 C. in analogy to a literature procedure yields alcohol 33a or chloride 33b [Stara, Irena G.; Stary, Ivo; Kollarovic, Adrian; Teply, Filip; Saman, David; Fiedler, Pavel. Coupling reactions of halobenzenes with alkynes. The synthesis of phenylacetylenes and symmetrical or unsymmetrical 1,2-diphenylacetylenes. Collect. Czech. Chem. Commun. (1999), 64(4), 649-672.].
Alternatively, the alkynes 33a or 33b can be prepared by Sonogashira reaction of the bromo-derivatives 32b with the corresponding alkynols or alkynechlorides.
Mesylation of alcohol 33a with methanesulfonylchloride e.g. in solvents such as pyridine or CH2Cl2 with bases like triethylamine or Huenig""s base optionally in the presence of DMAP (reaction step c) and subsequent amination (reaction step d) of the resulting mesylate 34 with a suitable amine NHA1A2 in a solvent like DMA, DMF or MeOH at RT or at 50-65xc2x0 yields the amine 6. Alcohol 33a can also be treated with trifluoromethane sulfonic acid anhydride and Huenig""s base at xe2x88x9215xc2x0 C. in CH2Cl2 (in situ generation of the corresponding triflate) followed by treatment with the corresponding amine NHA1A2 at xe2x88x9215xc2x0 C. to RT. This is especially the method of choice for but-3-yn-1-ol-derivatives 33a. Chloride 33b can be transformed directly or via iodide (Finkelstein reaction) to the amine 6, as described above (step d). Compounds 6 in which V is xe2x80x94CH2xe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94 can be obtained by hydrogenation of compound 6 in solvents like MeOH or EtOH with Pt2O.H2O or Pd/C (yields the saturated analogue 6) or by selective hydrogenation with other known methods (e.g. Lindlar or DIBAH, REDAL) (yields the double bond analogue 6). Optionally, the hydrogenation described above can be performed at an earlier stage e.g. the alcohol 33a or mesylate 34.
Alternatively, the group A1A2NC(A3A4C)-L-acetylene can be synthesised by known methods and attached to compound 32a or 32b (Sonogashira-coupling), to yield the compounds of the present invention 6 (reaction step f).
Compounds of the formula 5 (n greater than 0) may be synthesised by Swern oxidation of the alcohol 3 (Vxe2x95x90O and n greater than 0) to yield the corresponding aldehyde 35 (step g) as an intermediate. The aldehyde 35 may be treated with triphenylphosphine, tetra-bromo-methane and triethylamine in CH2Cl2 at 0xc2x0 C. to RT to yield 2,2-Dibromo-vinyl derivative 36 (step h). Rearrangement with n-BuLi (ca 1.6 M in hexane) in THF at xe2x88x9278xc2x0 C., followed by reaction with formaldehyde (xe2x88x9278xc2x0 C. to RT) leads to the propargyl alcohol 37a (step i, side chain extension through application of the Corey-Fuchs method), following conditions described in: Marshall, James A.; Bartley, Gary S.; Wallace, Eli M. Total Synthesis of the Pseudopterane (xe2x88x92)-Kallolide B, the Enantiomer of Natural (+)-Kallolide B. J. Org. Chem. (1996), 61(17), 5729-5735; and Baker, Raymond; Boyes, Alastair L.; Swain, Christopher J. Synthesis of talaromycins A, B, C, and E. J. Chem. Soc., Perkin Trans. 1 (1990), (5), 1415-21.
For longer side chains, the rearrangement is performed with n-BuLi (ca 1.6 M in hexane) in THF at xe2x88x9278xc2x0 C. as above, followed by addition of a co-solvens such as DMPU and reaction with O-protected 1-bromo-alcohols (e.g. 1-bromo-n-tetrahydro-pyaranyloxyalkane) to yield the O-protected compounds 37b (step i). O-protected compounds 37b can be deprotected to the corresponding alkynol 37a (in MeOH at 50-60xc2x0 C., in the presence of catalytic amount of pyridinium toluene-4-sulfonate). Alcohol 37a can be reacted with Huenig""s base/trifluoromethane sulfonic acid anhydride at xe2x88x9215xc2x0 C. in CH2Cl2 (in situ generation of the corresponding triflate) followed by treatment with Huenig""s base and the corresponding amine NHA1A2 at xe2x88x9215xc2x0 C. to RT to yield amine 6. Alternatively, mesylation of alcohol 37a with methanesulfonylchloride, pyridine and DMAP in CH2Cl2 at 0xc2x0 C. to RT yields mesylate 38. Conversion of the mesylate 38 to the amine 6 can be accomplished with an excess of the corresponding amine NHA1A2 in DMA at RT or as described above (step 1).
Compounds 6 in which V is xe2x80x94CH2xe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94 can be obtained by hydrogenation of compound 5 itself or the intermediates 37a, 37b or 38. The hydrogenation may be performed in EtOH or MeOH with Pt2O.H2O or Pd/C (yields the saturated analogues 6, 37a, 37b, or 38) or by selective hydrogenation to obtain the double bond by other known methods (e.g. Lindlar or DIBAH, REDAL) and transforming the intermediates afterwards to 6.
Alternatively, for the introduction of the group A1A2N(A3A4C)L in which A3 and/or A4 are not H, the following steps have to be performed starting from compound 36 (step m or steps i and l): for L=lower alkanes, the building block A1A2N(A3A4C)L-halogenide/mesylate is synthesised by known methods (or in analogy to the methods described in Scheme 2) and introduced (step m) under the same condition as described above for step i. For L=single bond, the introduction of the group A1A2N(A3A4C) with A3 and/or A4 not H, a two step procedure has to be followed: first the rearrangement of 36 with n-BuLi (ca 1.6 M in hexane) in THF at xe2x88x9278xc2x0 C., followed by reaction with the corresponding aldehyde (A3 or A4xe2x80x94COH) or ketone (A3COA4, at xe2x88x9278xc2x0 C. to RT) leads to the A3A4 substituted propargyl alcohol 37a (step i) which is e.g. mesylated or transformed to a phosphorester or a chloride (not shown) and reacted with the desired A1A2-substituted-amine in the presence of Tetrakis(triphenylphosphine)palladium (for the phosphorester) or Cu(I)Cl/Cu bronze and Huenig""s base (for the chloride) to yield the desired A3, A4-substituted compound 5 (step l ). (see: Bartlett, Paul A.; McQuaid, Loretta A. Total synthesis of (xc2x1)-methyl shikimate and (xc2x1)-3-phosphoshikimic acid. J. Am. Chem. Soc. (1984), 106(25), 7854-60 and Cooper, Matthew A.; Lucas, Mathew A.; Taylor, Joanne M.; Ward, A. David; Williamson, Natalie M. A convenient method for the aromatic amino-Claisen rearrangement of N-(1,1-disubstituted-allyl)anilines. Synthesis (2001), (4), 621-625.)
Amine 6 may be converted to a salt or to the N-oxide 6 using a mixture of hydrogen peroxide urea adduct and phthalic anhydride in CH2Cl2 at RT (step e).
If WA5 is a protecting group, this may be cleaved and the final moieties WA5 may be introduced as described for derivative 5 in scheme 1.
The following tests were carried out in order to determine the activity of the compounds of formula I and their salts.
Inhibition of Human Liver Microsomal 2,3-oxidosqualene-lanosterol Cyclase (OSC)
Liver microsomes from a healthy volunteer were prepared in sodium phosphate buffer (pH 7.4). The OSC activity was measured in the same buffer, which also contained 1 mM EDTA and 1 mM dithiothreitol. The microsomes were diluted to 0.8 mg/ml protein in cold phosphate buffer. Dry [14C]R,S-monooxidosqualene (MOS, 12.8 mCi/mmol) was diluted to 20 nCi/xcexcl with ethanol and mixed with phosphate buffer-1% BSA (bovine serum albumin). A stock solution of 1 mM test substance in DMSO was diluted to the desired concentration with phosphate buffer-1% BSA. 40 xcexcl of microsomes were mixed with 20 xcexcl of the solution of the test substance and the reaction was subsequently started with 20 xcexcl of the [14C]R,S-MOS solution. The final conditions were: 0.4 mg/ml of microsomal proteins and 30 xcexcl of [14C]R,S-MOS in phosphate buffer, pH 7.4, containing 0.5% albumin, DMSO less than 0.1% and ethanol less than 2%, in a total volume of 80 xcexcl.
After 1 hour at 37xc2x0 C. the reaction was stopped by the addition of 0.6 ml of 10% KOH-methanol, 0.7 ml of water and 0.1 ml of hexane:ether (1:1, v/v) which contained 25 xcexcg of non-radioactive MOS and 25 xcexcg of lanosterol as carriers. After shaking, 1 ml of hexane:ether (1:1, v/v) was added to each test tube, these were again shaken and then centrifuged. The upper phase was transferred into a glass test tube, the lower phase was again extracted with hexane:ether and combined with the first extract. The entire extract was evaporated to dryness with nitrogen, the residue was suspended in 50 xcexcl of hexane:ether and applied to a silica gel plate. Chromatographic separation was effected in hexane:ether (1:1, v/v) as the eluent. The Rf values for the MOS substrate and the lanosterol product were 0.91 and, respectively, 0.54. After drying, radioactive MOS and lanosterol were observed on the silica gel plate. The ratio of MOS to lanosterol was determined from the radioactive bands in order to determine the yield of the reaction and OSC inhibition.
The test was carried out on the one hand with a constant test substance concentration of 100 nM and the percentage OSC inhibition against controls was calculated. The more preferred compounds of the present invention exhibit inhibitions larger than 50%. In addition, the test was carried out with different test substance concentrations and subsequently the IC50 value was calculated, i.e. the concentration required to reduce the conversion of MOS into lanosterol to 50% of the control value. The preferred compounds of the present invention exhibit IC50 values of 1 nM to 10 xcexcM, preferrably of 1-100 nM.
The compounds of formula I and their pharmaceutically acceptable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions,
emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils.
The production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula I and their pharmaceutically acceptable acid addition salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers are, however, required in the case of soft gelatine capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
Usual stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
The dosage of the compounds of formula I can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 mg to about 1000 mg, especially about 50 mg to about 500 mg, comes into consideration for the prevention and control of topical and systemic infections by pathogenic fungi. For cholesterol lowering and treatment of impaired glucose tolerance and diabetes the daily dosage conveniently amounts to between 1 and 1000 mg, preferably 5 to 200 mg, for adult patients. Depending on the dosage it is convenient to administer the daily dosage in several dosage units.
The pharmaceutical preparations conveniently contain about 1-500 mg, preferably 5-200 mg, of a compound of formula I.
The following Examples serve to illustrate the present invention in more detail. They are, however, not intended to limit its scope in any manner.